Head and neck squamous cell carcinoma (HNSCC) is a deadly form of cancer that exhibits overactivation of the epidermal growth factor receptor (EGFR) pathway. However, anti-EGFR inhibitors have not significantly improved patients' survival rates. The long-term goal of this project is to define novel targets and therapeutic modalities that will help to circumvent acquired resistance to current EGFR inhibitors. Critical to maintaining the integrity of stratified epithelia such as the skin and oral cavity, desmosomes are essential intercellular adhesion junctions. Beyond their canonical function as adhesive molecules, our lab has shown that desmosomal components are involved in signaling pathways important in health and in disease, such as cancer. Desmoglein 1 (Dsg1), a desmosomal cadherin, promotes differentiation of keratinocytes by binding to its protein partner Erbin in orde to attenuate downstream EGFR effectors. EGFR activation depends on a localized burst of ROS and HNSCC tumors exhibit a high level of oxidative stress. These observations led me to focus on Dsg1's role in regulating redox signaling at the cell membrane, specifically by binding to an antioxidant enzyme, peroxiredoxin 1 (PRDX1). I hypothesize that Dsg1 inhibits ROS production at the cell membrane by binding to PRDX1 and maintaining its enzymatic activity in order to suppress EGFR activation. I will first determine the extent to which Dsg1 attenuates EGFR signaling in HNSCC cells via suppression of ROS induced by EGFR activation (Aim 1). The effect of Dsg1 expression on intracellular ROS level upon EGFR stimulation will be tested. In addition, oxidants will be used to challenge Dsg1's ability to attenuate phosphorylation of EGFR and its downstream effectors in the presence of excess ROS. Antioxidants will also be employed to determine their effects on attenuating the EGFR pathway in the absence of Dsg1. The second aim is to determine how the Dsg1-PRDX1 interactions affect EGFR signaling in HNSCC. I will test whether Dsg1 is required to bind to PRDX1 at the cell membrane in order to reduce membrane ROS and inhibit EGFR phosphorylation. Testing my central hypothesis will reveal the extent to which Dsg1 regulates the EGFR pathway via suppression of ROS, and will determine the function of a novel interaction between Dsg1 and PRDX1 in head and neck cancer cells. Elucidating the cross-talk between an adhesion molecule and redox signaling may improve HNSCC patient prognosis through interference with oxidative pathways as adjuvant therapy.